18-oxygenated pregnanes



2,982,767 18-0XYGENATED PREGNANES United States Patent O Park,Laboratories, Philadelphia, Pa., a corporation of Pennsylvania NoDrawing. Filed May 23, 1960, ser No. 30,772 14 Claims. (Cl. 260-23955)This invention relates to novel 18-oxygenated steroids. Morespecifically it pertains to compounds having the fundamental steroidalnucleus of the pregnane, allopregnane, 19-norpregnane or19-norallopregnane, and which in addition have an epoxide linkagebetween the carbon atom designated as -11 and the carbon atom furtherpossessing an oxygen function selected from the group consisting ofhydroxyl and oxo.

In general, the compounds of our invention are of the group consistingof steroids having the following structural formula:

wherein R is hydrogen or lower alkanoyl, R is hydrogen or fluoro, R, andR are methyl or hydrogen but not necessarily the same, R is methyl,fluoro, or hydrogen, at least one of groups R R, and R, being asubstituent other than hydrogen, and X is (H, OH) or O; and the1,2-bisdehydro analogs thereof.

The bonds represented by the symbol i indicate that both the a and ,6configuration of the groups so bound may be present and bothconfigurations of these groups are embraced by the present inventionwhen the bonds are sodesignated.

The compounds of our invention exhibit a high degree of diureticactivity, presumably by virtue of their ability to antagonize with thesodium retentive properties of aldosterone. They are thus valuablediuretic agents and are advantageously employed in congestive heartfailure,

ice

2 premenstral tension, nephrosis, cirrhosis of the liver, toxemic ofpregnancy and a variety of other edemic conditions.

The requisite starting materials for the preparation of our novelcompounds are prepared according to procedures described in ourcopending application Serial No. 842,615 filed September 28, 1959, nowUS. Patent #2,959,586, of which this application is acontinuationin-part. According to our present invention, a diacylate ofa l1,l8-oxidopregnane-20,21-diol of Formula II is first oxidized at 0-18by treatment with ruthenium tetraoxide to form the l1-hydroxy-l8-oicacid 11,18-lactone (III). Alternatively this oxidation is executed bytreatment of the 11,18-oxido compound with ozone, the process for whichis described in copending application Serial No. 23,631, filed April 21,1960. Unsaturation in the A-ring is next introduced by methods wellknown to the art. Thus for example, treatment with bromine in aceticacid yields the 2,4-dibromo derivative in the allopregnene series or the4-bromo derivative in the pregnane series. Subsequent treatment withsodium iodide and hydriodic acid or treatment with-collidine then yieldsthe 4-pregnene or 1,4-pregnadiene compounds respectively (IV).Alternatively the 1,4-pregnadienes may be prepared by methods well knownto the art such as treatment with selenium dioxide.

The resulting 3-keto-11-hydroxy-20,2l-diacyloxypregnen-18-oic acidll,l8-lactone and corresponding pregnadienes are next deacylated by mildhydrolysis such as with an alkali metal carbonate in aqueous methanol orethanol and the resultant 20,21-diol (V) then converted to the2l-triphenylmethyl other by treatment with chlorotriphenylmethane. 'Theformation of this group (hereafter referred to as the trityl group)occurs specifically at the primary alcohol group at 0-21.

Alternatively this hydroxyl group may be protected by selectivelyreacylated at 0-21 by treatment with approximately one equivalent of anacyl anhydride or acyl chloride in the presence of a tertiary base suchas pyridine.

The free hydroxyl group at 0-20 is next oxidized to an oxo functionemploying chromium trioxide in acid solution to give the3,20-diketo-11-hydroxy-21-triphenylmethyl-4-pregnene-l8-oic acid11,18-lactone (VII) or corresponding 1,4-pregnadiene.

The protective trityl group is then conveniently removed bytreatmentwith refluxing acetic acid and there is thus obtained3,20-diketo-11,21-dihydroxy-4- pregnene-lS-oic acid 11,18-lactone (VIII)or the corresponding 1,4-pregnadiene.

The 3,20-diketone thus obtained is then treated with an alkali metalbicarbonate or carbonate in refluxing droxy-4-pregnene-18-oic acid11,18-la'ctone (IXb) or the corresponding 1,4-pregnadienes .or1,4-isopregnadienes.

Those compounds of our invention wherein X comprises hydroxyl areprepared directly by reduction of the l8-oxo group with lithium aluminumhydride. The carbonyl functions in positions 3 and 20 are advantageouslyprotected through suitable means such as formation of the3,20-bisethylenedioxy derivative through treatment with ethylene glycolunder acidic conditions. The protective ethylenedioxy groups .are thenremoved after the reductive step by the usual methods, such as forexample, refluxing in mild acid, to yield the 3,20-diketo-1l,l8-oxido-ILZl-dihydroxy derivative (XI).

Reacylation of the 0-21 hydroxyl group may be executed in the usualmanner such as treatment with one equivalent of a lower alkanoic acidchloride or anhydride (XII).

This reaction sequence may be summarized as follows:

CHI

OCH

CHgOecyl CHIOICYI o e ilJ Howyl Ruthenium tetroxide 5 R1 1 0 2 oxidation0 i H i H 5 11 III 21) brommetlon 2) dehydrohalogenntion CHOH CHnOacylCH; O (5 CH3 l HOH (I; HOeeyl Y I basic hydrolsls i 4" l VI ltrltyletionCH 00 C CH 00 C H I CHI)! 2 a l)l a HOE l] =0 0- OC RI h "R: Y Y

chromte acid B; I 0 oxidation 0 VI VII acetic acid hydrolysis OHgOH0510B. CHQOH CHI CH1 6 0 CHI E (I; o

5-K: "RI i/ i !l mild alkaline i: l R: R; 0 O

0 treatment 5 i E B. Il Bl lxb 1x3 VIII lxb tormatlan In the abovereaction sequence, the groups R, R R and R are as above defined. Thesymbol Y appearing to 19-norpregnanes with the exception of formation ofthe 1,4 diene system, which, as is known to the art, results inaromatization of the A-ring in the 19-norpregnane series. 7

As stated aboy, the 2 1-esters of our novel compounds are also embracedwithin the scope of our invention. Representative of the acyl radicalswhich may thus be present are any of the pharmaceutically acceptablelower alkanoic acid radicals of less than 7 carbon atoms known to theart, as for example acetate, propionate, butyrate, t-butyrate and thelike. These may be prepared according to the usual methods employed inthe art.

The following examples, while not to be construed as defining the scopeof this invention, will further serve to typify the manner of ourinvention. 1

Example 1 .(A) A mixture of 10 g. of 6u-fluoro-ll,l8-oxido-20,2l-dipropionyloxy allopregnane-B-one, a slight excess over thestoichiometric amount of ruthenium tetroxide in carbon tetrachloride isheated at reflux for 8 hours. The solution is filtered hot and thenallowed to cool. 'Evaporation of the cooled solution or residue yields3-keto-6a-' fluoro-11fl-hydrnxy-20,2l-dipropionyloxy allopregnane-18-oic acid 11,18-lactone.

(B) A stirred solution of 9.6 g. of 3-keto-6a-iluoro-1lfi-hydroxy-20,2l-dipropionyloxy allopregnane 18 oic acid11,18-lactone, in 120 ml. of acetic acid is treated l 51) LiAlHireduction 2) dilu teaeld treatment on. v on 0-4513:

CHQOH XII sdlving 4.44 g. of bromine in .42 ml. of acetone, adding 354g. of sodium carbonate stirring and filtrating, and then adding 40 g. ofsodium iodide followed by a brief reflux period. The resulting mixtureis stirred for 2 /2 hours, then 7.4 g. of oxalic acid dehydrate is addedfollowed by refluxing for 1 hour. Ethyl acetate (400 ml.) and 1.1 ofwater are added and the layers separated. The organic layer is washedwith water, 5% aqueous sodium bicarbonate, and again with water. Thewashed organic layer is then stirred with g. of zinc dust and 2 ml. ofacetic acid is filtered and washed again. The filtrate is thenevaporated to 'a solid which is dissolved in 80 rnl. of ethanol andacidified with 6 ml. of acetic acid. After addition of 3 g. of GirardsReagent T, the solution is'boiled for 30 minutes, cooled to .20 C.,treated with 37% formaldehyde and allowed to stand for 25 minutes. Atthe end of this time the mixture is extracted with ethyl acetate and theaqueous layeracidified to pH 1 and allowed to stand for 2 hours afterwhich time it also extracted with ethyl acetate. 'The second ethylacetate extract is washed, dried and evaporated to give 3lceto-6a-fluoro-l1fi-hydroxy-20,2l-dipropionyloxy- 4-pregnene-18-oicacid 11,18-lactone.

(C). A mixture of 3-keto 6a-fluoro-1lfi-hydroxy-20,21-dipropionyloxy-4-pregnene-l8:oic acid 11,18 lactone and a solution of350 ml. of. aqueous methanol containiug 3 g. of potassium bircarbonateand 5 g. of potassium carbonate is reacted for 12 hours andisthenquenched with water. The solid which thus forms is collected byfiltration and dried to yield 3-ketO- 6 a -.fluoro 11.,20,21triol-4-pregnene-18Foic acid 1l,18-lactone. .,-.T o a solution of 4.2 g.of this compound in 200 ml. of dry pyridine is added 3.6 g. ofchlorotriphenylmethane and the mixture stirred for 72 hours at roomtemperature .To the mixwith 34 ml. of 1.79 M hydrogenbromide in aceticacid 75 turn is then added 5 ml.- of water and the mixture rewater. 7yield 3,20-diketo-6a-fiuoro-l l-hydroxy 21 triphenylduced to a residueunder reduced pressure. This residue is dissolved in 100 ml. ofmethylene chloride and the crystallized from methanol to yield3-keto-6a-fluoro-11, 20 dihydroxy 21 triphenylmethoxy 4 pregnene-18--oic acid 11,18-lactone. with 90 mg. of chromic acid in 2 ml. of aceticacid and This compound is then treated 2 ml. of water. After 2 hours asmall amount of ethanol was added and the reaction mixture is quenchedwith The solid is collected by filtration and dried tomethoxy-4-pregnene-l8-oic acid 11,18-lactone.

In a similar fashion by employing 3 keto 65 fluoro- I 11,18oxido-20,2l-dipropionyloxy allop egnane in the above reaction procedure,there is obtained 3.20-diketo- 65 fiuoro 115 hydroxy 21 triphenylmethoxy4 pregnene-lS-oic acid 11,18-lactone.

(D) Two grams of 3,20 diketo 6a fiuoro 115 hydroxy 21 triphenylmethoxy 4pregnene 18 oic acid 11,18-lactone is refluxed for thirty minutes with60 ml. of 80% acetic acid. The solution is then diluted with 400 ml. ofwater and cooled to C. The solution is filtered and the filtratesaturated with sodium chloride and extracted with chloroform. Thechloroform extract is then washed with water, dried and evaported toyield 3,20 diketo 6a fiuoro 115,2l-dihydroxy-4- pregne'ne-18-oic acid11,18-lactone. 7

One gram of 3,20 diketo 6a fiuoro -1 15,21 dihydroxy-4-pregnene-l8-oicacid 11,18 lactone is treated with .05 g. of sodium dissolved in 50 ml.of anyhydrous methanol at reflux for 1 hour. The mixture is then dilutedwith water and the methanol removed by evaporation under reducedpressure. The resultant solution is then extracted with methylenechloride and the organic extracts dried over sodium sulfate. Thedried'methariol chloride solution is reduced to a residue and the solidthus obtained placed on alumina chromatographic column and eluted withbenzene following by benzene containing increasing quantities of ether.There is thus obtained the separate isomeric compounds 3,20 diketo 6afiuoro 115,21 dihydroxy 4 isopregnene 18 oic acid 11,18-

lactone and 3,20 diketo 6a fluoro- 115,21-dihydroxy- 4-pregnene-18-oicacid 11,18-lactone.

In a similar manner the 65-fluoroisomer be subjected to this procedureobtaining 3,20 diketo 65 fluoro-115, 21 dihydroxy 4 isopregnene-18-oicacid 11,18-lactone and 3,20 diketo 65 fiuoro 115,21 dihydroxy 4pregnene-lS-oic acid 11,18-lactone.

Example 2 A solution of 1.2 g. of 3,20-diketo-6a-fluoro-115,21-dihydroxy-4-pregnene-18-oic acid 11,18-lactone, 250ml. of ethyleneglycol and 60 mg. of p-toluene sulfonic acid is heated at 80 C. under0.2 mm. pressure until the volume is reduced to 50 ml. The product isisolated by extraction with chloroform and concentration of thechloroform extracts to a solid residue. of the 3,20-bisethylene compoundin 100 ml. of purified dioxane is treated dropwise with 1.5 g. oflithium aluminum hydride in 150 ml. of anhydrous ether. The mixture isheated at reflux for minutes and cautiously treated with the 7 ml. ofwater. The reaction mixture is filtered and evaporated to give thehemi-acetal. One gram of this compound in ml. of dioxaue is treated with2 ml. of concentrated hydrochloric acid and 10 mi. of water. Afterstanding for 4 hours, the mixture is diluted with water and filtered togive 3,20-diketo-6afiuoro-l1,18-oxido-4-pregnene-18,21-diol.

In a similar manner the 6a-fluoro-4-isopregnene-l1,18- lactone may besubjected to the above procedure and there is thus obtained3,20-diketo-6a-fluoro11,18-oxide- 4-isopregnene-18,21-diol. Likewise the65fluoro isomers A solution of 900 mg. 60

of bOIh the 4-pregnene and 4-isopregnene compounds may be reducedaccording to this procedure, obtaining the compounds3,20-diketo-65-fluoro-11,18-oxido-4-pregnene- 18,21-diol and3,20-diketo-65-fluoro-11,18-oxido-4-iso- 6 pregnene-18,2l-diol.

Example 3 3 keto-65-methyl-1 1,18-oxido-20,2l-diacetoxy-pregnane issubjected to the reaction procedure described in Exdescribed, there isobtained 3-keto-65-methyl-115-hydrew-20,2l-diacetoxypregnane-18-oic acid11,18-lactone. Three grams of this compound in dimethylformamide aretreated dropwise with one molar equivalent of bromine in 15dimethylformamide until the bromine color persists. The mixture is thenquenched in water and filtered. The solid thus collected is heated withcollidine to give 3-keto-65- methyl 115 hydroxy 20,21 diacetoxy 4pregnene- 18-oic acid 11,18-lactone. The compound is then sub- 20 jectedto the reaction procedures of parts C and D of Example 1. Uponcompletion of the steps therein recited and purification in theprescribed manner, there are obtained 3,20-diketo-65-methyl-115,21dihydroxy-4- pregnene-18-oic acid 11,18-lactone and 3,20-diketo-65-methyl-115,2l-dihydroxy-4-isopregnene-l8-oic acid 11,18- lactone.

These compounds when subjected to the procedure prescribed in Example 2,are then converted to 3,20-diketo-65-methyl-1l,18-oxido-4-pregnene-18,21-diol and the corresponding4-isopregnene.

Example 4 By employing equivalent amounts of 3-keto-11,l8-oxide-16a-methyl-20,2l-diacetoxypregnane in the procedure of Example 3there are obtained upon completion of the steps therein recited thecompounds 3,20-diketo-l15, 21-dihydroxy-l6a-methyl-4-pregnene-l8-oicacid 11,18- lactone and 3,20-diketo-115,2l-dihydroxy-16a-methyl-4-isopregnene-lS-oic acid 11,18-lactone. These compounds are thensubjected to the reaction procedure of Example 2 and there are thusobtained 3,20-diketo-11,18-oxido-16- methyl-4-pregnene-18,21-diol andthe corresponding 4-isopre'gnene.

Example 5 3 keto-9a-fluoro-1l,18-oxide-20,2l-diacetoxyallopregnane (10g.) is subjected to the conversions described in Example 1. Completionof these steps then yields the desired 3,20 diketo9a-fiuoro-11fl,2l-dihyd.roxy-4-pregm Ilene-180i: acid 11,18-lactone and3,20-diketo-9u-fluoro- 115,21-dihydroxy-4-isopregnene-18-oic acidlactone. This compound is then subjected to the reaction procedures ofExample 2 and there are thus obtained3,20-diketo-9afluorol1,18oxido-4-pregnene-18,21-diol andthecorrespending 4-isopregnene.

Example 6 S-keto-l1,18-oxido-20,21-dia-etoxy-19-norallopregnane issubjected to the reaction procedure of Example 1 and there is obtainedupon purification in the prescribed manner 3,20-dikcto-115,21-dihydroxy-19-nor-4-pregnene- 18-oic acid 11,18-lactone and thecorresponding 4-isopregnene, These compounds are then subjected to thereaction procedure of Example 2 and there are thus obtained thecompounds 3,20-diketo-11,18-oxido-19-nor-4- pregnene-18,20-diol and thecorresponding 4-isopregnene.

In a similar manner 3-keto-6a-fluoro-l1,18-oxido-20,21-diacetoxy-19-norallopregnane is subjected to the procedures of Example 1and there is obtained the compounds 3,20 diketo6a-fluoro-115,2l-dihydroxy-l9-nor-4-pregnene-18-oic acid 11,18-lactoneand the corresponding 4- isoprcgnene. Further transformations accordingto the procedures of Example 2 then yields3,20-diketo-6afluoro-ll,l8-oxido-l9-nor-4-pregnene-l8,21-diol and the 7corresponding 4-isopregnene.

ample 1 part A. Upon completion of the steps therein Example 7 Asolution of 3 g. of 3-keto-1IB-hydroxy-lGa-methyl-20,2l-diacetoxyallopregnane-18-oic acid 11,18-lactone (obtained via theruthenium tetroxide oxidation performed in Example 4) in 150 ml. oft-butanol containing 1.5 ml. of glacial acetic acid is treated with 0.9g. of selenium dioxide by refluxing for 24 hours under nitrogen. Anadditional 900 mg. of selenium dioxide is added and the reflux periodrepeated. The suspension is filtered and the filtrate evaporated. Thefiltrate residue is dissolved in ethyl acetate and the solution washedwith successive portions of 5% potassium bicarbonate solution, waterammonium sulfate solution, cold 5% ammonium hydroxide solution, waterand 1% hydrochloric acid. The residue is dried and reduced to a residueto yield 3- keto-l lfi-hydroxy-16a-methy1-20,2l-diacetoxy-l,4-pregnadiene-18-oic acid 11,18-lactone. This compound is thensubjected to the procedure of parts C and D of Example 1 and there arethus obtained3,20-diketo-11p,21-dihydroxy-16a-methyl-1,4-pregnadiene-18-oic acid11,18-lactone and 3,20-diketo-1113,21-dihydroxy-l6a-methyl-1,4-isopregnadiene-18-oic acid 11,18-1actone.

Alternatively the 1,4-diene system is introduced by the followingmethod. 3 keto4-bromo-11fl-hydroxy-16amethyl-20,2l-diacetoxypregnane-18-oic acid1'1,18-la.ctone (1 g.) (prepared as an intermediate in Example 4) istreated with one molar equivalent of bromine as described in Example 1.The resultant dibromo compound is reacted with 15 ml. of collidine atreflux for 45 minutes. Ether is added to the cooled mixture and theethereal extracts washed with dilute sulfuric acid, water, and dried.This dried solution is then reduced to a residue comprising3-keto-1lp-hydroxy-16a-methyl-20,2ldiacetoxy-l,4-pregnadiene-1-8-oicacid 11,18-lactone.

In a similar fashion the 1,4-diene systems are introduced via one ofthese methods and products treated according to Example 1 parts C, D andthere are thus obtained the following compounds: 3,20-diketo-6a-fluoro113,2l-dihydroxy-1,4-pregnadiene-18-oic acid 11,18-lactone;3,20-diketo-6a-fluoro-l113,21-dihydroxy-1,4-isopregnadiene-lB-oic acid1l,l8-lactone;' 3,20-diketo-9a-fluoro-11,9,21-dihydroxy-l,4-pregnadiene-l8-oic acid 11.18-lactone; and3,20-diketo-9a-fluoro-l1B,21-dihydroxy-1,4-isopregnadiene-18-oic acid11,18-lactone;3,20-diketo-6fimethyl-11,8,21-dihydroxy-l,4pregnadiene-l8-oic acid 11,18-1actone; and 3,20-diketo-6fl-methyl-11,9,21-dihydroxy-1,4-isopregnadiene-18-oic acid 11,18-lactone.

The resultant 1,4-pregnadiene-11,18-lactones may then be reducedaccording to the procedure of Example 2. There are thus obtained thefollowing compounds; 3,20- diketoGa-fluoro-I1,18-oxido-1,4-pregnadiene-18,21-diol; 3,20diketo-6a-fluoro-11,18-oxido-1,4-isopregnadienc-l8, 21-diol; 3,20diketo-9a-fluoro-1l,l8-oxido-l,4-pregnadiene-18,21-diol;3,20-diketo-9a-fluoro-l1,18-oxido-l,4-isopregnadiene 18,21 diol; 3,20diketo-6fl-methyl-1L18- oxido 1,4 pregnadiene-18,21-diol; and3,20-diketo-6pmethyl-1 1,18-oxido-1,4-isoprcgnadiene-18,21-diol.

Example 8 3,20 diketo-l1,9,2l-dihydroxy-l6a-methyl-4-pregnene- 18-oicacid 11,18-lactone (1 g.) is subjected to the reaction procedure ofExample 8 and there is thus obtained upon purification in the prescribedmanner, 3,20-diketo- 16a methyl1lp-hydroxy-Z1-propionyloxy-4-pregnenel8-oic acid 11,18-lactone.

In a similar fashion other lower alkauoic acid anhy-.

drides and/or other pregnenes, isopregnenes, pregnadienes orisopregnadienes may be employed in this procedure. There is thusprepared for example, 3,20-d1keto- 1 1,18-lactone;3,20-diketo-1lp-hydroxy-Zl-propionyloxy- 4-pregnene-18-oic acid 11,18-lactone; 3,20-diketo-9afluoro1lp-hydroxy-Zl-butyryloxy-1,4-pregnadiene-18-oic acid 1 1,18-lactone.

We claim:

1. 3,20-diket0-6-flu0ro-11fi,2l dihydroxy 1,4-pregnanene-18,21-diol.

11. 3,20-diketo-6fl-methyl-11fi,21-dihydroxy-1,4 pregnadiene-18-oic acid11,18-lactone.

12. 3,20-diketo-6p-methyl-1L18 oxido 4 pregnene 18,21-dio1.

13. 3,20-diketo-6fi-methyl-11,18-oxido-1,4 -pregnadiene- 18,21-diol.

14. 3,20-dilreto-1 1,18-oxido-16a-methyl -4 isopr-egneue- 18,21-diol.

References Cited in the file of this patent UNITED STATES PATENTS2,838,542 Spero et a1 June 10, 1958 2,838,548 Magerlein et a1. June 10,1958 2,867,632 Lincoln et al. Ian. 6, 1959 2,875,200 Hogg et a1 Feb. 24,1959 2,897,218 Sebek et al July 28, 1959 2,934,543 Reichstein et al Apr.26, 1960 OTHER REFERENCES Wieland et al.: (1) Helv. Chim. Acta 41,316-440 (1958), pages 419 and 424 are depended upon.

Wieland et al.: (2) Helv. Chim. Acta 43, 617-623 (1960), pages 617 and618 depended upon.

Heusler et al.: Experientia 16, 21-24 (Jan. 1, 1960).

1. 3,20-DIKETO-6-FLUORO-11B,21 - DIHYDROXY - 1,4-PREGNADIENE-18-OIC ACID11,18-LACTONE.
 2. 3,20-DIKETO-6-FLUORO-11,18 - OXIDO - 1,4 -PREGNADIENE18,21-DIOL.